Collagenous sprue is associated with high morbidity; however, the etiology of this disorder is unclear. Data regarding the pathological and clinical manifestations of patients with collagenous sprue are also limited. We, thus, undertook this study to gain insight into the etiology, disease manifestations and outcomes of collagenous sprue. We searched our departmental database (1999-2008) to identify cases of collagenous sprue and to obtain clinical and laboratory data. Small bowel histology, including thickness of subepithelial collagen, intra-epithelial lymphocyte phenotype and results of T-cell clonality assays were evaluated. Nineteen patients (15 women, 4 men, age 22-80 years, mean 57 years) were identified. Seventeen (89%) had celiac disease and two had unclassified sprue; 9 of 17 (53%) celiac disease patients had refractory disease; 5 of 15 (33%) lacked diarrhea (atypical presentation), including 2 of 6 (33%) with active (untreated) celiac disease and 3 of 9 (33%) with refractory celiac disease. Autoimmune disorders were seen in 12 of 19 (63%) patients and microscopic colitis (n=7), lymphocytic gastritis (n=2) or collagenous gastritis (n=2) were seen in nine patients. Subepithelial collagen thickness was mildly (n=6), moderately (n=10), or markedly (n=3) increased and villous atrophy was total (n=13) or subtotal (n=6). Phenotypically aberrant intraepithelial lymphocytes were not detected in any case. Polymerase chain reaction analysis showed a dominant T-cell clone in the only patient with refractory celiac disease type II. Histological improvement occurred in 7 of 11 (64%) patients. Overall, 8 of 19 (42%) responded to gluten-free diet, including 2 of 9 (22%) with refractory celiac disease and 10 responded to immunomodulatory therapy, including 6 of 9 (67%) with refractory celiac disease. Only one patient died from complications of refractory celiac disease. No patient developed lymphoma. The vast majority of our patients with collagenous sprue had celiac disease. Although, many patients required immunomodulatory therapy for symptom control, a subset responded to gluten-free diet alone. In our experience, collagenous sprue patients had relatively good clinical outcomes.